There are many differences between females and males in the brain, behavior, and disease. One of these is established in rodents as well as man: spatial memory. What could be the underlying basis? In this project we test the hypothesis that there are robust sex differences in the rodent medial entorhinal cortex that could explain sex differences in spatial memory. The medial entorhinal cortex seems a logical candidate given it is critical to spatial representation in the rat, and lies in an ideal anatomical position because it is situated between hippocampus and cortex. Our preliminary data, using slices of entorhinal cortex, shows a sex difference in evoked responses to afferent input in entorhinal cortex: in slices from females, responses are repetitive or prolonged relative to males, a sex difference that is blocked by the NMDA receptor antagonist D-APV. When estrogen levels are high, these events are most robust, and when estrogen is low, or a prepubertal animal is evaluated, they are relatively rare. We hypothesize that the responses of entorhinal neurons to afferent input are increased in the female rat relative to males, and this disrupts information processing and synaptic plasticity, i.e., long-term potentiation (LTP). Because the difference appears to be localized to superficial layers, the perforant path projection to hippocampus may be selectively influenced, and this is important because the perforant path is the major afferent system to hippocampus from entorhinal cortex. In this proposal, we will establish the cellular physiology in slices of entorhinal cortex of female and male rats, test sex differences in LTP in the entorhinal cortex and hippocampus, and address whether puberty and estrogen are key factors, as Preliminary data suggest. Together the results will shed light on an area of the brain where sex differences are relatively unexplored, and could have important implications for understanding cognitive function, as well as treating learning disorders. PUBLIC HEALTH RELEVANCE This project will evaluate whether sex differences exist in a part of the brain where they have not previously been recognized, the entorhinal cortex, and address their implications. We hypothesize that there is increased neuronal activity in the female medial entorhinal cortex and this disrupts processing of new information, particularly spatial information. Based on Preliminary findings, estrogen appears to play a key role by facilitating NMDA receptor mediated activation of entorhinal neurons. The implications are important because they could help address sex differences in cognitive function, and lead to new considerations for treatment of learning disorders.